Directed therapy for patients with myelodysplastic syndromes (MDS) by suppression of cyclin D1 with ON 01910.Na

Title
Directed therapy for patients with myelodysplastic syndromes (MDS) by suppression of cyclin D1 with ON 01910.Na
Author(s)
곽민정Matthew J. Olnes[Matthew J. Olnes]Aarthie Shenoy[Aarthie Shenoy]Barbara Weinstein[Barbara Weinstein]Loretta Pfannes[Loretta Pfannes]Kelsey Loeliger[Kelsey Loeliger]Zachary Tucker[Zachary Tucker]Xin Tian[Xin Tian]Francois Wilhelm[Francois Wilhelm]Agnes S.M. Yong[Agnes S.M. Yong]
Keywords
SCORING SYSTEM; UP-REGULATION; CD34 CELLS; PHASE-I; EXPRESSION; TRISOMY-8; SURVIVAL; LEUKEMIA; EFFICACY; ABNORMALITIES
Issue Date
201208
Publisher
PERGAMON-ELSEVIER SCIENCE LTD
Citation
LEUKEMIA RESEARCH, v.36, no.8, pp.982 - 989
Abstract
Background: We previously demonstrated upregulation of c-myc, survivin, and cyclin D1 in CD34+ bone marrow mononuclear cells (BMMNCs) of patients with trisomy 8 and monosomy 7 myelodysplastic syndromes (MDS). "Knockdown" of cyclin D1 by RNA interference decreased trisomy 8 cell growth, suggesting that this might be a therapeutic target in MDS. Experimental design: We performed preclinical studies using BMMNCs from patients with MDS and AML to examine the effects of the styryl sulfone ON 01910.Na on cyclin D1 accumulation, aneuploidy, and CD34+ blast percentage. We next treated twelve patients with higher risk MDS and two trisomy 8 AML patients with ON 01910.Na on a phase I clinical protocol (NCT00533416). Results: ON 01910.Na inhibited cyclin D1 expression, and was selectively toxic to trisomy 8 cells in vitro. Flow cytometry studies demonstrated increased mature CD15+ myeloid cells and decreased CD34+ blasts. Three patients treated with ON 01910.Na on a clinical had decreased bone marrow blasts by >= 50%, and three patients had hematologic improvements, one of which was sustained for 33 months. Patients with hematologic responses to ON 01910.Na had decreased cyclin D1 expression in their CD34+ cells. Conclusions: The preclinical results and responses of patients on a clinical trial warrant further investigation of ON 01910.Na as a potential novel targeted therapy for higher risk MDS patients. Published by Elsevier Ltd.
URI
http://hdl.handle.net/YU.REPOSITORY/27529http://dx.doi.org/10.1016/j.leukres.2012.04.002
ISSN
0145-2126
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이과대학 > 통계학과 > Articles
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